PROJECT SUMMARY Alcohol use disorder (AUD) and overweight/obesity (OOB) are highly prevalent conditions that contribute substantially to global disease burden. Alongside recent increases in the prevalence of AUD and alcohol- attributable mortality, projections indicate that up to one half of U.S. adults will live with obesity by the end of this decade. Because each condition confers increased risk for numerous chronic health conditions, those with co-occurring alcohol use disorder and overweight/obesity (AUD-OOB) are at increased risk for negative health outcomes. The emergence of highly effective incretin-based therapies for diabetes and OOB, including glucagon-like-peptide 1 (GLP-1) receptor agonists, is rapidly expanding the range of effective treatments for those with OOB and cardiometabolic disorders. Moreover, preclinical findings and clinical observations suggest that GLP-1 receptor agonists can reduce alcohol consumption. Tirzepatide, the first dual GLP-1 and GIP (glucose-dependent insulinotropic polypeptide) receptor agonist, shows superior efficacy for weight loss compared to the most effective GLP-1 receptor mono-agonists. Tirzepatide (Zepbound) received FDA approval for the treatment of overweight/obesity in November 2023. Recent findings further show that tirzepatide has protective effects on cardiovascular risk outcomes and projected risk of cardiovascular disease. Based on epidemiological trends and the high prevalence of metabolic conditions in those with alcohol use disorder, an increasing number of heavy drinkers are likely to receive treatment with tirzepatide. Should tirzepatide prove effective for reducing alcohol consumption, the identification of a treatment for co-occurring alcohol use disorder and overweight/obesity could achieve significant long-term health impact. The aim of this study is to expedite clinical research on dual GLP-1/GIP receptor agonists in participants with AUD-OOB by conducting a Phase II randomized trial of tirzepatide. Adults with AUD-OOB will be recruited for a double-blind, between- subjects trial using dose-escalating treatment with tirzepatide (Zepbound) over 8 weeks. Prospective changes in alcohol use, weight, and cardiometabolic outcomes will be measured at weekly clinic visits. By expediting clinical research on tirzepatide, a new treatment poised for widespread clinical use, this project will position the field for larger clinical trials of dual GLP-1/GIP receptor agonists as potential treatments for co-occurring AUD and OOB.